Glutamate transporter xCT is important for cGAS-dependent interferon responses to DNA and to HSV-1

2026 · doi:10.64898/2026.04.28.721347
preprint OA: closed
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⚙ AI-generated deep summary by claude@2026-06, 2026-06-24 · read from full text ⓘ

The paper studied how metabolic reprogramming and glutamate transport regulate innate antiviral signaling, using HSV-1 infection and cytosolic DNA stimulation to trigger cGAS-STING responses in cells. It found that HSV-1 infection and cytosolic DNA induce export of glutamate via the xCT (SLC7A11) transporter, and that inhibiting xCT reduces DNA-induced cGAMP production, thereby weakening type I interferon (IFNα/β) responses and interferon-stimulated gene induction, which corresponded with increased viral replication. The authors also reported that altering intracellular glutamate levels through other pathway inhibitors (glutaminolysis or glutamate import) modulated IFN responses, and that HSV-1 suppresses xCT expression through an ICP27-dependent mechanism to promote viral replication. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Metabolic reprogramming is a key component of antiviral immunity, yet how metabolite transport regulates innate immune signaling remains incompletely understood. Here, we show that infection with herpes simplex virus 1 (HSV-1) and stimulation with cytosolic DNA induce the cellular export of glutamate via the xCT (SLC7A11) transporter and that inhibition of xCT reduces cellular resistance to viral replication. Mechanistically, xCT inhibition impaired cGAS-STING signaling by reducing DNA-induced cGAMP production, thereby diminishing type I interferon (IFNα/β) responses and downstream induction of interferon-stimulated genes. Interestingly, modulating intracellular glutamate levels through inhibition of other glutamate pathways, e.g., glutaminolysis or glutamate import, also affected cellular IFN responses, suggesting that glutamate is a central control knob for DNA sensing. Finally, we demonstrate that HSV-1 suppresses xCT expression via a mechanism dependent on the immediate early viral protein ICP27, thereby promoting viral replication by limiting cGAS-dependent IFN induction. Together, these findings identify xCT-dependent glutamate transport as a critical metabolic regulator of cGAS-STING-mediated antiviral immunity.
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Abstract Metabolic reprogramming is a key component of antiviral immunity, yet how metabolite transport regulates innate immune signaling remains incompletely understood. Here, we show that infection with herpes simplex virus 1 (HSV-1) and stimulation with cytosolic DNA induce the cellular export of glutamate via the xCT (SLC7A11) transporter and that inhibition of xCT reduces cellular resistance to viral replication. Mechanistically, xCT inhibition impaired cGAS-STING signaling by reducing DNA-induced cGAMP production, thereby diminishing type I interferon (IFNα/β) responses and downstream induction of interferon-stimulated genes. Interestingly, modulating intracellular glutamate levels through inhibition of other glutamate pathways, e.g., glutaminolysis or glutamate import, also affected cellular IFN responses, suggesting that glutamate is a central control knob for DNA sensing. Finally, we demonstrate that HSV-1 suppresses xCT expression via a mechanism dependent on the immediate early viral protein ICP27, thereby promoting viral replication by limiting cGAS-dependent IFN induction. Together, these findings identify xCT-dependent glutamate transport as a critical metabolic regulator of cGAS-STING-mediated antiviral immunity.

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last seen: 2026-05-20T01:45:00.602351+00:00